Despite their increased risk of developing serious diseases including coronary heart disease, Type 2 diabetes, hypertension, certain types of cancers, and stroke, the public health crisis of individuals who are overweight or obese continues unabated. Safety issues have hampered development of drugs designed to control weight, and the four drugs currently on the market in the U.S. each has side effects that either limits their use to the very obese or prevents them from gaining wide acceptance in patients. Development of new weight loss drugs that are safe and effective with no undesirable side effects remains an important public health goal. Leptin is a hormone secreted by white adipocytes and regulates the amount of fat stored in the body by adjusting both the sensation of hunger and by adjusting energy expenditures. While Amgen did not succeed in its efforts to gain regulatory approval of recombinant human leptin as a treatment for obesity (BMI 27-37), their studies and those of many others since have yielded a wealth of information regarding the reasons for this outcome. Overwhelming evidence suggests that clinical trials with the hormone failed due to the phenomenon of leptin resistance appearing in obese patients, especially those with BMIs at the upper end of the scale. Computational modeling based on cerebrospinal fluid and serum levels of leptin indicates that in obese individuals (BMI>30, leptin levels of about 40 ng/ml), the inability of the hormone to cross the blood-brain barrier (BBB) accounts for almost two-thirds of this resistance. It is expected that a form of leptin capable of reaching its receptos in the brain would be an effective therapy for the overweight and mildly obese, which accounts for the majority of those at risk for type 2 diabetes. Intranasal administration of leptin at the cribriform plate, known as intranasal-to-brain (INB) delivery, enables leptin to enter the brain without exposure to plasma proteases or exclusion by the BBB. NeuroNano Pharma, Inc. is developing a novel formulation of human leptin (hu-leptiPOL-N) in which a single polymer chain of the poloxamer, Pluronic(r) P85, is covalently attached to the N-terminus of the protein. In preliminary studies, a closely related murine leptin analog with a single P85 chain randomly attached one of the free amino groups of the protein exhibited lower activity (~14-fold) as compared to native leptin but displayed a remarkable ability for uptake in brain hypothalamus following INB administration (about 4 times higher than that observed with native leptin). We propose to optimize the poloxamer modification to produce a more active hu-leptiPOL-N that, following INB administration, will exhibit greater receptor activation while retaining the property of uptake in the brain (and brain hypothalamus). The overall goal is to provide preclinical evidence that hu-leptiPOL-N, administered intranasally, is effective in treating overweight and obesity in the diet-induced obese (DIO) mouse model. If the optimized hu-leptiPOL-N demonstrates superiority to native leptin in brain hypothalamic delivery and in feeding studies in DIO mice, we will initiate a development plan to culminate in an IND to commence clinical studies.